Therapies For Rare Diseases Research Articles

Inclusion of Infants and Neonates in Pediatric Orphan Product Approvals.

The Orphan Drug Act (ODA) of 1983 was enacted to provide financial incentives to drug sponsors to develop therapies for rare diseases. Although this act increased the number of orphan products approved, there are still a limited number of products available for the pediatric population because orphan drug products are exempt from the Pediatric Research Equity Act. The objectives of this study were (i) to evaluate the pediatric orphan drug studies submitted to the US Food and Drug Administration (FDA) in the period of 2007-2018 and (ii) to examine whether orphan drug products were fully labeled with a pediatric indication in infants and neonates. Out of the 468 indications evaluated, 171 (37%) were FDA-labeled for use in the pediatric population. Labeling for the 12 to <18years age group was most common (98%). Fifty-two percent of FDA-labeled pediatric indications included the newborn to <2years of age group. In this newborn to <2years age group, the indication was labeled without pivotal clinical trials in 43% of the programs. Of the 60 new indications not labeled down to birth, 50% were found to have an age of onset and diagnosis that occurs earlier than the age approved for use of the product for that indication. In summary, although the ODA has been successful in improving pediatric access to medications for rare diseases, our analysis identified the incomplete labeling for pediatric patients under 2years of age. Strategies to include the birth to <2years old group of pediatric patients in orphan drug development programs should be explored.

Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases

BackgroundOrphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a “broad disease” categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades.ResultsBetween 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%.ConclusionsAnalysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.

An analysis of member retention patterns for adult rare disease cohorts to support evaluating multiyear payment arrangements for novel therapies.

BACKGROUND: Traditionally, treatment for chronic conditions addressed symptoms or was disease modifying and required lifelong periodic administration and recurring costs. Cell and gene therapies for rare diseases often require a short administration period relative to their expected long-term clinical benefit. Costs have historically been recognized when the service or treatment is administered, resulting in the potential for the cost associated with the possible long-term clinical benefit of cell and gene therapies being incurred during a short administration period. Innovative payment arrangements have been proposed to improve the synchronization of the payment and the emergence of the clinical benefit. Expected payments associated with a multiyear payment arrangement will depend on many factors, but key drivers of the payments include efficacy, durability of effect, mortality, and member retention. This research extends a previous study by analyzing member retention for adult patients with certain rare diseases. OBJECTIVE: To develop member retention estimates from a US commercial payer's perspective for adults diagnosed with certain rare diseases during a 10-year period. METHODS: Four population cohorts were examined: (1) self-insured - all subscribers, (2) self-insured - rare medical condition, (3) fully insured - all subscribers, and (4) fully insured - rare medical condition. Seven rare medical conditions were prospectively selected: cerebral palsy, cystic fibrosis, Gaucher disease, hemophilia, sickle cell disease, spina bifida, and thalassemia. We limited the study cohort to members who were either the subscriber or the subscriber's partner and were aged 18 years or older; dependent children were excluded from the analysis, regardless of age. The IBM MarketScan Commercial Claims and Encounters research database for the 10 years ending December 31, 2016, was used as the basis for the analysis. The analysis was completed using the lifetest procedure available in version 9.4 of the SAS Software System for Windows. The Kaplan-Meier method was used to produce retention rates. A log-rank test with chi-square statistic was used to determine statistically significant differences between pairs of curves. RESULTS: The study found that the subscriber retention for the rare medical condition cohort is significantly higher than the all-subscribers cohort by at least 12 points at each 1-year period. The finding was statistically significant (P < 0.0001) for the self-insured and fully insured cohorts. At year 5, approximately 20% more of the rare medical condition cohort was retained as compared with the all-subscribers cohort regardless of payer type. In addition, the study found that the probability of retention for adults with each rare medical condition in the rare disease cohort was also statistically significantly higher than all subscribers regardless of payer type. CONCLUSIONS: In multiyear payment arrangements, it may be important to set expectations for member retention based on studies specific to particular member cohorts. Health insurers and plan administrators may have inaccurate expectations if standard assumptions based on all member populations are used. This study found that adults diagnosed with 1 of 7 rare medical conditions are retained longer, on average, than all adult subscribers. DISCLOSURES: Milliman received funding from bluebird bio for the conduct of this study and fees from AveXis, outside the submitted work. Jackson, Runyan, and Metz are employed by Milliman. Jackson and Metz are members of the American Academy of Actuaries and meet the qualification standards for performing the analyses in this report. Kenney is an independent managed care consultant and received consulting fees from Milliman during the conduct of this study; Kenney also serves as preceptor for the Massachusetts College of Pharmacy and Health Sciences, is immediate past president of the Academy of Managed Care Pharmacy, and is a member of the Massachusetts Pharmacists Association Legislative Committee.

Gene therapy may not be as expensive as people think: challenges in assessing the value of single and short-term therapies.

At an upfront price of $2.125 million, the one-time gene therapy onasemnogene abeparvovec for spinal muscular atrophy, a rare neuromuscular disorder that is usually fatal by 2 years of age if untreated, has been called the "most expensive drug ever." This flawed characterization raises important methodological and policy issues regarding valuation of high-cost treatments. We reviewed several other high-cost therapies-with a particular focus on hemophilia A treatment-studied by the nonprofit Institute for Clinical and Economic Review (ICER). In ICER's summary report of 2 treatments for managing hemophilia A, published in this month's JMCP issue, the estimated $15-$18 million lifetime cost of factor VIII is characterized as "far too high," representing "a failure of competition [that] … builds a platform for pricing of treatments … that will only exacerbate these problems." Current literature indicates several factors underlying high factor VIII treatment cost (eg, historical pattern of innovation and lack of market competition) that may also drive the pricing dynamics of advanced therapies for other rare diseases. When a treatment's price is driven high (or "distorted"), an economic principle known as "theory of the second best" suggests that market price becomes a poor estimate of social opportunity cost, and adjustments should be made for such distortions. In any case, a high-cost standard of care creates an opportunity for new technology to generate cost savings, providing an inducement for market entry. Recognizing that this potentially creates a tendency to produce price distortions for new treatments, ICER has attempted to apply some ad hoc adjustments. However, challenges remain in creating a "level playing field" across different disease-modifying or potentially curative innovations (eg, one-time therapy vs ongoing or lifelong treatment with repeated doses). While additional policy work is needed to address this dilemma, it would clearly be misleading to assume that gene therapies are inherently expensive. Rigorous economic evaluation of novel therapies requires careful comparison of lifetime cost and benefits vs standard of care, including adjustments for pricing distortions. Fortunately, economic theory suggests that we could adjust to this circumstance by using the social opportunity costs of interventions based on an appropriate variable cost-effectiveness threshold that would be higher for rare severe diseases. DISCLOSURES: The research reported in this Viewpoints article was funded by Novartis Gene Therapies, Inc. Garrison and Jiao were paid by Novartis Gene Therapies, Inc., to conduct this research. Garrison has also received consulting fees from BioMarin, Inc, and UniQure. Dabbous is a full-time employee of Novartis Gene Therapies, Inc., and holds Novartis stock and stock options.

Anion-exchange HPLC assay for separation and quantification of empty and full capsids in multiple adeno-associated virus serotypes

Gene therapy has entered a new era where numerous therapies for severe and rare diseases are generating robust and compelling clinical results. The rapid improvements in gene therapies over the past few years can be attributed to better scientific understanding of the critical quality attributes that contribute to a safe and efficacious product, as well as a better understanding of the manufacturing processes that are required to yield consistent products, which routinely meet the quality standards required for clinical studies. Of particular concern is the need for an effective, quality control (QC)-compatible, and versatile test method for the quantification of empty and full capsids in recombinant adeno-associated virus (rAAV) samples from multiple serotypes. In that regard, we describe the development of a QC-compatible anion-exchange chromatography method consisting of a modular discontinuous gradient to achieve full baseline peak separation and quantification of empty and full AAV capsids. Using an rAAV6 vector, our assay was shown to be precise, linear, robust, and accurate—correlating well with orthogonal methods such as analytical ultracentrifugation (AUC) and cryogenic transmission electron microscopy (Cryo-TEM). Additionally, we demonstrate the versatility of our approach by adapting the method to separate and quantify empty/full capsids in samples from several rAAV serotypes.

European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER)

Patients with rare diseases often receive insufficient medical care. The European Reference Networks (ERNs) were initiated by the European Union to improve healthcare for patients with rare and complex diseases within Europe. The Reference Network on Hepatological Diseases (ERN RARE-LIVER), which consists of hepatological centres, scientific societies and numerous patient organizations, is one of 24ERNs. The aim of ERN RARE-LIVER is high-quality healthcare for patients suffering from rare liver diseases, regardless of their place of residence. Standardization of treatment, coordination of research projects as well as training and teaching of patients, patient representatives and healthcare professionals are means to reach this goal. Virtual case discussions are offered via aweb-based platform (Clinical Patient Management System), in which experts from the ERNs advise treating physicians on the diagnosis and therapy of rare diseases.

Stakeholder perspectives on clinical research related to therapies for rare diseases: therapeutic misconception and the value of research

BackgroundFor many rare diseases, few treatments are supported by strong evidence. Patients, family members, health care providers, and policy-makers thus have to consider whether to accept, recommend, or fund treatments with uncertain clinical effectiveness. They must also consider whether and how to contribute to clinical research that may involve receiving or providing the therapy being evaluated.ObjectiveTo understand why and how patients and families with rare metabolic diseases, specialist metabolic physicians, and health policy advisors choose whether to participate in studies and how they use and value research.MethodsWe conducted separate focus group interviews with each stakeholder group (three groups in total); two groups were conducted by telephone and the third was held in-person. Participants were recruited using purposive sampling. We analyzed each interview transcript sequentially using a qualitative description approach to inductively identify key themes. Several strategies to ensure credibility and trustworthiness were used including debriefing sessions after each focus group and having multiple team members review transcripts.ResultsFour patients/caregivers, six physicians, and three policy advisors participated. Our findings did not support conventional perspectives that therapeutic misconception (gaining access to treatment) is the main motivating factor for patients/caregivers to participate in clinical research. Rather, patients’/caregivers’ expressed reasons for participating in research included advancing science for the next generation and having an opportunity to share their experiences. Patients/caregivers and physicians described the difficulties in weighing risks versus benefits of accepting treatments not well-supported by evidence. Physicians also reported feeling conflicted in their dual role as patient advisor/advocate and evaluator of the evidence. Policy advisors were primarily focused on critically appraising the evidence to make recommendations for the health system.ConclusionsStakeholders differ in their perspectives on rare disease research but share concerns about the risks versus benefits of therapies when making individual- and population-level decisions.

Regulatory environment for novel therapeutic development in mitochondrial diseases.

At present, there is just one approved therapy for patients with mitochondrial diseases in Europe, another in Japan, and none in the United States. These facts reveal an important and significant unmet need for approved therapies for these debilitating and often fatal disorders. To fill this need, it is critical for clinicians and drug developers to work closely with regulatory agencies. In the United States, mitochondrial disease patients and clinicians, the United Mitochondrial Disease Foundation, and pharmaceutical industry members have engaged with the Food and Drug Administration to educate each other about these complex and heterogeneous diseases and about regulatory requirements to obtain approvals for novel therapies. Clinical development of therapies for rare diseases has been facilitated by the 1983 US Orphan Drug Act (ODA) and similar legislation in Japan and the European Union. Further legislation and regulatory guidance have expanded and refined regulatory flexibility. While regulatory and financial incentives of the ODA have augmented involvement of pharmaceutical companies, clinicians, with patient advocacy groups and industry, need to conduct natural history studies, develop clinical outcome measures, and identify potential supportive surrogate endpoints predictive of clinical benefit, which together are critical foundations for clinical trials. Thus, the regulatory environment for novel therapeutic development is conducive and offers flexibility for mitochondrial diseases. Nevertheless, flexibility does not mean lower standards, as well-controlled rigorous clinical trials of high quality are still required to establish the efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. This process is illustrated through the authors' ongoing efforts to develop therapy for thymidine kinase 2 deficiency.

Necessity and limitations of paediatric research—a personal view

: The objective of this review is to present a personal view on the need of paediatric research and its practical and ethical boundaries. The review is based on the personal experience of a senior paediatric neurologist and head of a research ethics committee, taking into account selected references. In summary, the physical and psychological immaturity and developmental potential of children, especially at a young age, require specific, age-appropriate research methods and topics that differ from research on adults. Worldwide, many children still die from common and treatable diseases such as measles and pneumonia. On the other hand, new lifestyle-dependent diseases such as allergies, attention deficit disorder and obesity are rapidly increasing in number in industrialised countries. With the gradual elucidation of the genetic causes of rare diseases, interest in their treatment is also increasing. The necessary research includes age-related physiological and pathophysiological, pharmacological, psychosocial, educational, epidemiological and socio-economic studies. However, young children are not able to understand complex instructions and follow study protocols, which makes it difficult to conduct reliable and valid studies. In addition, the rarity of many paediatric diseases and the different age groups often require national and supranational research groups with the associated high costs. As children have limited capacity to understand and consent to the risks and benefits of their participation, they are considered particularly vulnerable persons who need to be protected in all types of research in accordance with international ethical regulations and laws. In conclusion, as research on children tends to be more complex and less often refinanced, public and private sponsors, regulators and public health systems are called upon to support the necessary research on children in any way they can. This is not only about developing new therapies for rare diseases in developed countries, but also affordable therapies for common diseases in poorer regions of the world.

Derivation of Induced Pluripotent Stem Cell (iPSC) Lines from Patient-Specific Peripheral Blood Mononuclear Cells (PBMC) Using Episomal Vectors.

Inherited retinal diseases (IRDs) are a diverse group of rare eye disorders, resulting in vision loss or blindness. The underlying reason is mutation in one or more than 250 different genes associated with the development and normal physiology of retina largely comprising of rod/cone photoreceptors and retinal pigment epithelium. Interestingly, the sub retinal region of an eye has been shown to be immune privileged, broadening the scope of cell-replacement therapies for patients suffering from retinal degeneration. Several groups around the globe, including ours, have demonstrated safety and efficacy in preclinical studies by employing various approaches of retinal cell therapy. This had largely been possible with the advent of induced pluripotent stem cells (iPSC)-reprogrammed from adult somatic cells, that serves as a starting material for generating retinal cells de novo. Here, we describe a detailed procedure for reprogramming peripheral blood mononuclear cells (PBMC) into iPSC using episomal vectors without any physical disruption in the host genome. The lines thus created were tested for sterility, cytogenetic stability, identity, absence of episomal plasmids and further authenticated for pluripotency and tri-lineage differentiation capacity by embryoid body formation and immunocytochemistry. We believe that this feeder-cell free, animal-product free and gene-insertion free protocol would help people to develop and bank patient-specific cell lines for autologous cell therapies for incurable rare diseases.

Pathways from Immune Profiling to Therapies for Rare Diseases

Single-cell transcriptomic profiling has enhanced the description of several diseases. Beyond improving our understanding of the pathophysiology of these diseases, these approaches can lead to clues about therapeutic approaches. In a recent issue of Cell, Wang et al. describe immune perturbations in livers of biliary atresia patients that implicate specific autoimmune pathways of disease.1.

PP355 Evolution Of Health Technology Assessment For Rare Diseases In Asia

IntroductionWe reviewed the health technology assessment (HTA) guidelines for therapies targeting orphan conditions in four countries/regions in Asia.MethodsA pragmatic literature search was conducted to identify and review key documents outlining reimbursement, pricing, and coverage policies in China, Taiwan, Korea, and Japan.ResultsTherapies for rare diseases in Japan and those for ultra-rare diseases in Korea are exempt from cost-effectiveness evaluations. Taiwan provides full financial coverage for rare disease therapies. China has no special considerations for rare diseases. Drugs included in the medical insurance list are reimbursed at varying levels depending on the “class” of the listing. Unlike prior variations at provincial levels for coverage of off-the-list drugs, new national policy has introduced consistency in coverage.ConclusionsAccess and reimbursement processes vary between markets in Asia. New HTA guidelines in Japan allow for easier access to therapies targeting rare diseases by eliminating cost-effectiveness analysis for price determination. On the other hand, a value dossier including an economic evaluation is necessary for rare diseases in Korea. However, manufacturers can provide risk-sharing schemes for rare diseases. China has not yet introduced any specific evaluations or reimbursement criteria for therapies targeting rare diseases. Policies for rare diseases are evolving rapidly to improve access and affordability.

Current state of developing advanced therapies for rare diseases in the European Union

ABSTRACT Objective Advanced Therapy Medicinal Products (ATMPs) present significant therapeutic advantages for inherited rare diseases. However, the development of orphan ATMPs is challenging due to their complexity and unpredictable biological activity. This study aims to comprehensively describe the current state of orphan ATMPs in Europe. Methods Orphan drugs (ODs) granted by European Commission until March 2020 were investigated. The characteristic of diseases and ATMPs were extracted from the public summary reports of ODs from Committee for Orphan Medicinal Products. The methodology for the pivotal studies of ATMPs was extracted. Results A total of 274 ATMPs were identified, covering 116 rare diseases, with metabolic, optical, and oncologic diseases being the most targeted. A total of 158 ATMPs were indicated for life-threatening diseases, 129 ATMPs targeted diseases currently lacking authorized or satisfactory treatment available. Twenty-eight ATMPs are being investigated in the phase II/IIII or phase III studies. The median patient size of pivotal studies was 127, 15 were open-label studies, 8 were single-arm trials, and 14 reported surrogate outcomes. Conclusion There are rapid growths in developing ATMPs for life-threatening diseases with high unmet clinical needs. Optimizing the study methodology and exploring innovative design to facilitate the market access is paramount.

Curative gene therapies for rare diseases

Diseases caused by alterations in the DNA can be overcome by providing the cells or tissues with a functional copy of the mutated gene. The most common form of gene therapy implies adding an extra genetic unit into the cell. However, new genome engineering techniques also allow the modification or correction of the existing allele, providing new possibilities, especially for dominant diseases. Gene therapies have been tested for 30 years in thousands of clinical trials, but presently, we have only three authorised gene therapy products for the treatment of inherited diseases in European Union. Here, we describe the gene therapy alternatives already on the market in the European Union and expand the scope to some clinical trials. Additionally, we discuss the ethical and regulatory issues raised by the development of these new kinds of therapies.

Supplemental appraisal processes required for rare disease therapy?

Supplemental appraisal processes required for rare disease therapy?

Long-chain fatty acid oxidation disorders: managed care and specialty pharmacy implications

Long-chain fatty acid oxidation disorders (LC-FAODs) represent a group of rare inborn errors of metabolism characterized by acute crises of energy metabolism and severe energy deficiency. Clinical manifestations include rhabdomyolysis, liver dysfunction, severe hypoglycemia, and cardiomyopathy. The symptoms associated with these genetic disorders may result in frequent hospitalizations and early death. Many patients with LC-FAODs experience major clinical events and significant morbidity and mortality that portends a substantial need for better therapeutic options for these disorders. Triheptanoin was recently approved for the treatment of LC-FAODs. As with any novel agent for rare diseases, the treatment adoption and coverage criteria for rare disease therapy such as this presents challenges for managed care decision makers. Both managed care decision makers and specialty pharmacists must ensure that healthcare professionals provide appropriate patient and caregiver education surrounding the management of LC-FAODs, including vital information on adopting emerging agents into the therapy armamentarium for these disorders.

Genome Editing for Rare Diseases.

Significant numbers of patients worldwide are affected by various rare diseases, but the effective treatment options to these individuals are limited. Rare diseases remain underfunded compared to more common diseases, leading to significant delays in research progress and ultimately, to finding an effective cure. Here, we review the use of genome-editing tools to understand the pathogenesis of rare diseases and develop additional therapeutic approaches with a high degree of precision. Several genome-editing approaches, including CRISPR/Cas9, TALEN and ZFN, have been used to generate animal models of rare diseases, understand the disease pathogenesis, correct pathogenic mutations in patient-derived somatic cells and iPSCs, and develop new therapies for rare diseases. The CRISPR/Cas9 system stands out as the most extensively used method for genome editing due to its relative simplicity and superior efficiency compared to TALEN and ZFN. CRISPR/Cas9 is emerging as a feasible gene-editing option to treat rare monogenic and other genetically defined human diseases. Less than 5% of ~7000 known rare diseases have FDA-approved therapies, providing a compelling need for additional research and clinical trials to identify efficient treatment options for patients with rare diseases. Development of efficient genome-editing tools capable to correct or replace dysfunctional genes will lead to novel therapeutic approaches in these diseases.

Tackling rare diseases: Clinical trials on chips.

Designing and conducting clinical trials are extremely difficult in rare diseases. Adapting tissue chips for rare disease therapy development is pivotal in assuring that treatments are available, especially for severe diseases that are difficult to treat. Thus far, the NCATS-led National Institutes of Health (NIH) Tissue Chip program has focused on deploying the technology towards in vitro tools for safety and efficacy assessments of therapeutics. However, exploring the feasibility and best possible approach to expanding this focus towards the development phase of therapeutics is critical to moving the field of CToCs forward and increasing confidence with the use of tissue chips. The working group of stakeholders and experts convened by NCATS and the Drug Information Association (DIA) addresses important questions related to disease setting, test agents, study design, data collection, benefit/risk, and stakeholder engagement-exploring both current and future best use cases and important prerequisites for progress in this area.

Shifting clinical trial and value demonstration models for cell and gene therapies: present & future critical success factors

Background & Aim Clinical trial models have been changing over the past decade, influenced by emergence of innovative technologies, increasing focus on subgroups and niche populations, competition over patients, and need to capture transformative health outcomes. Approximately half of rare disease and oncology therapies today are launched from fast-track pathways with a single-arm study, creating challenges in shaping a comprehensive value proposition sufficient to meet the needs of clinicians, regulators and payers. In addition, uncertainties remain around demonstration of transformative magnitude, duration and patient-centric effects, which require strong data-analytic and real-world evidence development strategies. This session will discuss how the evolution of clinical trial models is shifting us towards requirements to consider a comprehensive approach to value demonstration that meets provider, regulator, payer decision needs. Methods, Results & Conclusion Mr. Faulkner will open the session by reviewing key clinical design issues in cell and gene therapy trials and common gaps that must be filled outside the trial, including leveraging outcomes research and real-world evidence solutions, highlighting recent global research on cell and gene therapy regulatory and HTA decisions in North America and the EU. Dr. Theocharous will consider key clinical trial design and execution best practices from a manufacturer perspective, drawing from common development challenges, and Dr. Koh will compliment this with clinical trial and patient treatment considerations from the perspective of a practicing physician executing cell and gene therapies in the field. Mr. Morgese will discuss recent US and EU policy issues that flow from cell and gene therapy evidence issues and highlight steps that the cell and gene therapy community are taking to address. The panel will debate the top critical success factors necessary for linking clinical trial designs to other gap-fill strategies to meet downstream approval, access and uptake requirements.

CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases: A Review.

Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders that share a great deal of homology in terms of genetic etiologies and symptoms. Disruption of genetic or epigenetic mechanisms can cause issues with regulating the expression of imprinted genes, thus leading to disease. Genetic mutations affect the imprinted genes, duplications, deletions, and uniparental disomy (UPD) are reoccurring phenomena causing imprinting diseases. Epigenetic alterations on methylation marks in imprinting control centers (ICRs) also alters the expression patterns and the majority of patients with rare IDs carries intact but either silenced or overexpressed imprinted genes. Canonical CRISPR/Cas9 editing relying on double-stranded DNA break repair has little to offer in terms of therapeutics for rare IDs. Instead CRISPR/Cas9 can be used in a more sophisticated way by targeting the epigenome. Catalytically dead Cas9 (dCas9) tethered with effector enzymes such as DNA de- and methyltransferases and histone code editors in addition to systems such as CRISPRa and CRISPRi have been shown to have high epigenome editing efficiency in eukaryotic cells. This new era of CRISPR epigenome editors could arguably be a game-changer for curing and treating rare IDs by refined activation and silencing of disturbed imprinted gene expression. This review describes major CRISPR-based epigenome editors and points out their potential use in research and therapy of rare imprinting diseases.